C-14 oxidation of morphine derivatives

ABSTRACT

The present invention relates to process for the preparation of a 14-hydroxynormorphinone derivative of formula IV 
                         
comprising reacting the compound of formula III,
 
                         
with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant;
 
wherein R 1  is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
 
R 2  is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen.
 
     The process is very suitable in the production of noroxymorphone.

The invention relates to a process for the production of14-hydroxynormorphinone derivatives, to a new synthetic route forproducing noroxymorphone, as well as to new intermediates in said route.

Noroxymorphone is a key intermediate for the production of importantmedicinal opioids, such as naltrexone and naloxone. The common startingmaterial for the production of these opioids is thebaine from which theyare readily synthesized. However, thebaine has only a low naturalabundance in poppy heads and opium. As the supply of thebaine is limitedand the demand is increasing, many alternative approaches have been madefor the preparation of 14-hydroxymorphine derivatives. See for exampleEP 0,158,476, U.S. Pat. No. 5,922,876, and the references cited therein.

Further, in an attempt to remove the requirement for (the preparationof) thebaine, Coop et al. (Tetrahedron 55 (1999), 11429-11436; WO00/66588) recently described an oxidative method for the production of14-hydroxycodeinone in a yield of 51% from codeinone, using Co(OAc)₃ asthe metallic oxidant in acetic acid at room temperature. Other oxidativeconditions with metallic oxidants, such as Co(OAc)₃ under otherconditions, FeCl₃, Co(OAc)₂ in combination with several cooxidants,RuO₄, Mn(OAc)₃, Cu(OAc)₂, and others, proved to be not very usefulaccording to Coop.

Surprisingly, and in spite of the findings of Coop, it has now beenfound that in the production of 14-hydroxynormorphinone derivatives offormula IV from compounds of formula III cobalt (II) salts can be usedas efficient oxidants when the reaction is performed in the presence ofa mild base and oxygen or air is used as cooxidant. Therefore, theinvention relates to a process for the preparation of a14-hydroxynormorphinone derivative of formula IV

comprising reacting the compound of formula III,

with a cobalt (II) oxidant in the presence of a mild base and air oroxygen as the cooxidant; wherein R₁ is (1-7C)alkyl optionallysubstituted with one or more chlorines (such as 1,1,1-trichloroethyl),butenyl, vinyl, benzyl, phenyl or naphthyl;and R₂ is benzyl or benzyl substituted with one or more (1-6C)alkoxygroup or benzyl substituted with one or more halogen.

The oxidation process of the present invention is an efficient processwith good yields, which are significantly improved when compared to theprocess described by Coop et al.

The cobalt (II) oxidant according to the present invention may beselected from a range of cobalt (II) salts, such as CoF₂, CoCl₂, CoBr₂,Co(II)sulfate, Co(II)nitrate, Co(II)acetate, Co(II)propionate, and thelike, and mixtures thereof. The preferred oxidant in the process of thisinvention is Co(OAc)₂ and the preferred cooxidant is air. The reactionmixture of this oxidation process is a heterogeneous system; the oxidantdissolves only in minor amounts in the organic solvent that is used. Theamount of cobalt (II) salts used is not very critical, as long as thesystem is heterogeneous, and a skilled person will know to choosesufficient amounts thereof. The cooxidant is introduced into thereaction mixture by bubbling it through the solution, while stirring.

A person skilled in the art is aware what type of base are meant withthe term mild bases, however preferred bases are sodium acetate,potassium acetate, sodium phosphate and potassium phosphate. Mostpreferred is sodium acetate.

Preferably R₁ is (1-7C)alkyl, and most preferred is ethyl. For R₂ benzylis most preferred. The oxidation process according to the presentinvention is performed in an organic solvent well-suited for dissolutionof this type of compounds, preferably (1-4C)alcohols or mixturesthereof. Preferred is ethanol.

The reaction temperature is usually higher than room temperature, andmay be chosen dependent on the boiling point of the solvent used.However, the temperature may not be higher than about 100° C. in orderto keep the oxygen sufficiently in solution.

In the terms (1-7C)alkyl, (1-6C)alkoxy and (1-4C)alcohols the alkylgroup is a branched or unbranched alkyl group having 1 to 7, 1 to 6 or 1to 4 carbon atoms, respectively, such as methyl, ethyl, isopropyl,t-butyl, heptyl and the like.

The compound of formula III may suitably prepared by methods well knownin the art. Preferably, the process for the preparation of a compound offormula III comprises reactively contacting a morphine derivative offormula II

with an oxidizing agent effective for oxidizing allylic hydroxy groupsto form keto groups, where a morphinone compound of the formula III isprepared. Preferably, the oxidizing agent is sodium dichromate.Preferably R₁ is ethyl. For R₂ benzyl is most preferred.

The new process of this invention may conveniently be used in theproduction of noroxymorphone. Therefore, another aspect of thisinvention is a process for the production of noroxymorphone, comprisinga reaction step wherein a morphinone compound of formula III is oxidizedinto the 14-hydroxynormorphinone derivative of formula IV. In particularpreferred is the process further comprising the oxidation of a morphinederivative of formula II into the compound of formula III as describedabove.

Especially preferred is a process for the production of noroxymorphonecomprising the steps:

(a) converting morphine having the formula I

 by reaction with a haloformate ester of the formula X—C(═O)OR₁, whereinR₁ is as previously defined and X is a halogen (F, Cl, Br or I,preferably Cl), followed by a reaction with R₂—X, wherein X (preferably Cl) and R₂ areas previously defined, to form a morphine derivative of formula II;(b) oxidizing the morphine of formula II to form a morphinone derivativeof formula III according to the previously described process;(c) oxidizing the morphinone derivative of formula III to form a14-hydroxynormorphinone derivative of formula IV according to thepreviously described process;(d) deprotecting the 3-position and (at the same time) reducing thedouble bond at the 7,8-position of the 14-hydroxynormorphinonederivative of formula IV to form a 3,14-hydroxynormorphinone derivativeof formula V, using methods well known in the art for such type ofreaction, e.g. using hydrogen and palladium-carbon as a catalyst,

(e) and hydrolyzing the 3,14-hydroxynormorphinone derivative of formulaV into noroxymorphone of formula VI, using methods well known in the artfor such type of hydrolysis, e.g. using sulfuric acid,

In the process for the production of noroxymorphone, the novelintermediates of formula II, III and IV form each another aspect of thepresent invention. The intermediates of formula II, III and IV are inparticular preferred wherein R₁ is ethyl. Also preferred areintermediates of formula II, III and IV wherein R₂ is benzyl. Mostpreferred are the intermediates of formula II, III and IV wherein R₁ isethyl and R₂ is benzyl.

The invention is further illustrated by the following example.

EXAMPLE 1

The underlined numbers refer to the numbers of the structures of SchemeI. (Bn=benzyl).

(5α,6α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-6-hydroxymorphinan-17-carboxylicacid ethylester (2)

Morphine (1, 8 g) was dissolved in 80 ml of toluene and the solution wasdried by azeotropic distillation of water. Sodium carbonate (15 g) andsodium hydrogen carbonate (6 g) were added and the solution was againdried by azeotropic distillation. Ethyl chloroformate (30 g) was slowlyand in portions added over a period of approximately 4 h at 78° C.Completion of the reaction was checked with TLC. The excess of reagentand the salts were dissolved by addition of water. The layers wereseparated and the toluene layer was washed with water. The toluenesolution was evaporated to dryness and the residue was dissolved in 70ml of ethanol. The 3-carboxylic acid ethyl ester group was saponified by6 g potassium hydroxide (dissolved in 18 ml of ethanol) and 5 gpotassium carbonate at 55° C. The pH was checked (in a 1:1 dilution inwater) and was >11. To this basic solution 5 g benzylchloride was addedand the reaction was performed for 4 h at 75° C. The product wasprecipitated by the addition of water (70 ml), filtered, washed withwater and dried. The yield of product (2) was 10 g. ¹H NMR (600 M,CDCl₃) δ 1.29 (m, 3H), 1.92 (m, 2H), 2.52 (s, 1H), 2.72 (m, 2H), 2.85(m, 1H), 3.01 (m, 1H), 4.01 (m, 1H), 4.17 (m, 3H), 4.87 (d, 1H), 4.89(d, 1H), 5.09 (d, 1H), 5.18 (d, 1H), 5.29 (t, 1H), 5.72 (t, 1H), 6.53(d, 1H), 6.75 (d, 1H), 7.37 (m, 5H).

(5α)-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-6-oxomorphinan-17-carboxylicacid ethylester (3)

A solution of Jones reagent was prepared by dissolving 7,5 g sodiumdichromate.2H₂O in 22 ml water and 6 ml sulfuric acid. Compound (2) (7,5g) was dissolved in 60 ml trichloro ethylene and 28 ml water was added.The pH was adjusted to 5 with sulfuric acid. The mixture was heatedunder reflux and the Jones reagens was slowly added over a period of 1h. The oxidation was continued for another 1,5 h under reflux. Theexcess of oxidant was destroyed with 6 ml 2-propanol. The layers wereseparated and the organic layer was washed with 10% sodium hydrogencarbonate solution and water and dried with sodium sulfate. The solutionwas evaporated to dryness and the residue was dissolved in ethanol.Yield: ˜9 g product (3). ¹H NMR (200 MHz, CDCl₃) δ 1.28 (m, 3H), 1.92(m, 2H), 2.8 (m, 2H), 2.9 (m, 1H), 4.02 (m, 1H), 4.19 (m, 2H), 4.72 (s,1H), 5.03 (m, 1H), 5.18 (s, 2H), 6.12 (dd, 1H), 6.57 (d, 1H), 6.64 (in,1H), 6.74 (d, 1H), 7.34 (m, 5H).

(5α-3-(benzyloxy)-7,8-didehydro-4,5-epoxy-14-hydroxy-6-oxomorphinan-17-carboxylicacid ethylester (4)

The solution of product (3) in ethanol (9 g in 135 ml) was heated to 60°C., 2,6 g cobalt (II) acetate and 0,5 g sodium acetate were added andair was bubbled through the solution under vigorous stirring. Thereaction was followed with TLC. After completion of the reaction thesolution was treated with charcoal (0,3 g) and filtered. The solutionwas distilled to volume and this concentrated solution (6,3 g (4) in 53ml of ethanol) was transferred to the next step. ¹H NMR of 4 (360 MHz,CH₃OH-d4) δ 1.28 (m, 3H), 1.55 (m, 1H), 2.52 (m, 1H), 2.74 (m, 1H), 2.92(m, 2H), 4.05 (m, 1H), 4.15 (m, 2H), 4.64 (m, 1H), 4.72 (s, 1H), 4.85(m, 1H), 5.1 (s, 2H), 6.05 (d, 1H), 6.6 (d, 1H), 6.76 (d, 1H), 6.91 (m,1H), 7.3 (m, 5H).

(5α)-4,5-epoxy-3,14-dihydroxy-6-oxomorphinan-17-carboxylic acidethylester (5)

To the solution of the previous step 6 ml of acetic acid was added. Theproduct (4) was reduced with hydrogen and palladium-carbon (5%) as acatalyst (0,9 g) at 20° C. and normal pressure. After filtration andevaporation of ethanol 5,4 g of crude product (5) was obtained. Theproduct was recrystallized from 2 parts (w/v) of ethyl acetate to obtain4,7 g product (5).

(5α)-4,5-epoxy-3,14-dihydroxymorphinan-6-one (noroxymorphone) (6)

Product (5) (4,7 g) was dissolved in 28 ml of water and 5,6 ml ofsulfuric acid and refluxed for approx. 24 h. The product wasprecipitated at pH=9 by dilution with water and 4,6 g of crude product(6) was obtained after filtration and drying. The product was purifiedby dissolution in ethanol, precipitation from this solvent at pH=2,dissolution in water, charcoal treatment and precipitation at pH=9. ¹HNMR (400 M z, DMSO-d6) δ 1.17 (m, 1H), 1.41 (m, 1H), 1.72 (m, 1H), 2.07(m, 1H), 2.29 (m, 1H), 2.36 (m, 1H), 2.62 (in 1H), 3.9 (m, 4H), 6.52 (d,1H), 6.56 (d, 1H).

1. A process for the preparation of a 14-hydroxynormorphinone compoundof formula IV

comprising reacting the compound of formula III,

with a cobalt (II) oxidant in the presence of a mild base and air oroxygen as the cooxidant; wherein R₁ is (1C-7C)alkyl optionallysubstituted with one or more chlorines, butenyl, vinyl, benzyl, phenylor naphthyl; and R₂ is benzyl or benzyl substituted with one or more(1C-6C)alkoxy group or benzyl substituted with one or more halogen. 2.The process of claim 1, wherein the oxidant is Co(OAc)₂.
 3. The processof claim 1, wherein the cooxidant is oxygen.
 4. The process of claim 1,wherein the mild base is sodium acetate, potassium acetate, sodiumphosphate or potassium phosphate.
 5. The process of claim 4, wherein themild base is sodium acetate.
 6. The process of claim 1, wherein R₁ is(1-7C)alkyl.
 7. The process of claim 6, wherein R₁ is ethyl.
 8. Theprocess of claim 1, wherein R₂ is benzyl.
 9. A 14-hydroxynormorphinonecompound of the formula IV

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen.
 10. The 14-hydroxynormorphinonecompound of claim 9, wherein R₁ is ethyl.
 11. The14-hydroxynormorphinone compound of claim 9, wherein R₂ is benzyl.
 12. Amorphinone compound of the formula III

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen.
 13. The morphinone compound ofclaim 12, wherein R₁ is ethyl.
 14. The morphinone compound of claim 12,wherein R₂ is benzyl.
 15. A process for the preparation of a compound offormula III

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen, comprising: reactively contactinga morphine compound of formula II

wherein R₁ and R₂ are as defined above, with an oxidizing agenteffective for oxidizing allylic hydroxy groups to form keto groups, toform the compound of formula III.
 16. The process of claim 15, whereinthe oxidizing agent is sodium dichromate.
 17. The process of claim 15,wherein R₁ is ethyl.
 18. A process for the production of noroxymorphone,comprising: a reaction step wherein a morphinone compound of formula III

is oxidized into a 14-hydroxynormorphinone compound of formula IV

with a cobalt (II) oxidant in the presence of a mild base and air oroxygen as the cooxidant; wherein R₁ is (1C-7C)alkyl optionallysubstituted with one or more chlorines, butenyl, vinyl, benzyl, phenylor naphthyl; and R₂ is benzyl or benzyl substituted with one or more(1C-6C)alkoxy group or benzyl substituted with one or more halogen. 19.The process of claim 18, further comprising reactively contacting acompound of formula II

wherein R₁ is (1C-7C)alkyl optionally substituted with one or morechlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R₂ is benzylor benzyl substituted with one or more (1C-6C)alkoxy group or benzylsubstituted with one or more halogen, with an oxidizing agent effectivefor oxidizing allylic hydroxy groups to form keto groups, to form amorphinone compound of formula III wherein R₁ and R₂ are as definedabove.
 20. A process for the production of noroxymorphone, whereinmorphine having the formula I

is converted into noroxymorphone, comprising: (a) converting morphinehaving the formula I by reaction with a haloformate ester of the formulaX—C(=O)OR₁, wherein R₁ is (1C-7C)alkyl optionally substituted with oneor more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl and X is ahalogen, followed by a reaction with R₂—X, wherein X is as previouslydefined and R₂ is benzyl or benzyl substituted with one or more(1C-6C)alkoxy group or benzyl substituted with one or more halogen, toform a morphine compound of formula II

wherein R₁ and R₂ are as defined above, (b) oxidizing the morphine offormula II to form a morphinone compound of formula III wherein R1 andR2 are as defined above, wherein the process is reactively contacting amorphine compound of formula II with an oxidizing agent effective foroxidizing allylic hydroxy groups to form keto groups; (c) oxidizing themorphinone compound of formula III with a cobalt (II) oxidant in thepresence of a mild base and air or oxygen as the cooxidant to form a14-hydroxynormorphinone compound of formula IV wherein R₁ and R₂ are asdefined above; (d) deprotecting the 3-position and reducing the doublebond at the 7,8-position of the 14-hydroxynormorphinone compound offormula IV to form a 3,14-hydroxynormorphinone compound of formula V,

wherein R₁ is as defined above; (e) and hydrolyzing the3,14-hydroxynormorphinone compound of formula V into noroxymorphone offormula VI,


21. The process of claim 1, wherein the cooxidant is air.
 22. Theprocess of claim 15, wherein R₂ is benzyl.